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Cutaneous melanoma is an aggressive form of skin cancer derived from skin melanocytes and is associated with significant morbidity and mortality. A significant fraction of melanomas are associated with precursor lesions, benign clonal proliferations of melanocytes called nevi. Nevi can be either congenital or acquired later in life. Identical oncogenic driver mutations are found in benign nevi and melanoma. While much progress has been made in our understanding of nevus formation and the molecular steps required for transformation of nevi into melanoma, the clinical diagnosis of benign versus malignant lesions remains challenging., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None to declare.

A patient with woolly hair nevus syndrome, presented with epidermal facial nevi by the age of 12 years. Despite transient improvement with topical 1% sirolimus cream, the facial nevus grew larger. The patient was then treated with topical 1% everolimus cream resulting in a reduction in the size of the nevus. This case highlights a novel use of topical 1% everolimus cream, which previously has not been used to treat epidermal nevi., (© 2024 Wiley Periodicals LLC.)

Epidermal nevi are common benign cutaneous hamartomas that may rarely demonstrate histopathologic evidence of epidermolytic hyperkeratosis (EHK), representing cutaneous mosaicism for pathogenic keratin variants. Rarely, individuals with linear epidermal nevi transmit to their children the inherited form of EHK, also known as epidermolytic ichthyosis, characterized by generalized erythema, blistering, and scaling at birth evolving to widespread hyperkeratosis. We present an updated review of reported cases of linear epidermal nevi with EHK exhibiting transmission of epidermolytic ichthyosis to guide important considerations in the care of individuals with epidermal nevi. Clinical characteristics of linear epidermal nevi do not reliably predict the presence of EHK. All reported cases of transmission to offspring have occurred in individuals with linear epidermal nevi involving more than one anatomic area suggesting increased reproductive risk with involvement of two or more anatomic sites. Therefore, genetics consultation is recommended for these individuals with biopsy-confirmed EHK. For individuals with smaller areas of epidermal nevus involvement, the implications are less well known, though genetics consultation may still be considered for those interested in further discussion of general reproductive risk., (© 2024 The Author(s). Pediatric Dermatology published by Wiley Periodicals LLC.)

Porokeratotic adnexal ostial nevus (PAON) is a rare adnexal hamartoma characterized by keratotic papules following Blaschko's lines, typically located on the unilateral distal extremities. Cutaneous somatic GJB2 mutations have been linked to the pathogenesis of PAON. However, the genetic mechanism underlying bilateral or extended forms, which are less documented, remains unknown. In this study, we presented two cases of PAON with widespread cutaneous lesions and scalp involvement, and demonstrated the presence of GJB2 mosaic mutations in both patients. We further investigated the mosaic frequency in different tissues to gain insights into the mutation events contributing to the phenotype of widespread PAON. Our findings suggest that early postzygotic mutation causing mosaic GJB2 mutations may contribute to the widespread phenotype of PAON, thereby enriching the disease spectrum and mutation profile of PAON., (© 2024 Japanese Dermatological Association.)

SOLAMEN syndrome is a rare, recently recognized congenital syndrome that is characterized by progressive and hypertrophic diseases involving multiple systems, including segmental overgrowth, lipomatosis, arteriovenous malformation (AVM) and epidermal nevus. According to literatures, SOLAMEN syndrome is caused by heterozygous PTEN mutation. Phenotypic overlap complicates the clinical identification of diseases associated with PTEN heterozygous mutations, making the diagnosis of SOLAMEN more challenging. In addition, SOLAMEN often presents with segmental tissue overgrowth and vascular malformations, increasing the possibility of misdiagnosis as klipple-trenaunay syndrome or Parks-Weber syndrome. Here, we present a case of a child presenting with macrocephaly, patchy lymphatic malformation on the right chest, marked subcutaneous varicosities and capillaries involving the whole body, overgrowth of the left lower limb, a liner epidermal nevus on the middle of the right lower limb, and a large AVM on the right cranial thoracic entrance. Based on the typical phenotypes, the child was diagnosed as SOLAMEN syndrome. detailed clinical, imaging and genetic diagnoses of SOLAMEN syndrome was rendered. Next-generation sequencing (NGS) data revealed that except for a germline PTEN mutation, a PDGFRB variant was also identified. A subsequent echocardiographic examination detected potential cardiac defects. We suggested that given the progressive nature of AVM and the potential severity of cardiac damage, regular echocardiographic evaluation, imaging follow-up and appropriate interventional therapy for AVM are recommended., (© 2024. The Author(s).)

Melanocytes derived from neural crest cells harbor the BRAF V600E mutation, which is the predominant driver of nevus formation in humans. This mutation leads to malignant cell proliferation and subsequent cell cycle arrest, culminating in oncogene-induced senescence and nevus development. Nevertheless, emerging evidence has highlighted the heterogeneity of cellular senescence markers in BRAF V600E -induced senescent melanocytes. Moreover, the capacity of melanocytes within nevi to regain their proliferative ability raises questions about the molecular mechanisms by which BRAF V600E , via the mitogen-activated protein kinase signaling pathway, triggers nevus formation. This study provides an overview and discussion of the molecular mechanisms underpinning BRAF V600E -induced melanocyte nevus formation and the relevant animal models employed for their elucidation. It also highlights the significance of elucidating dynamic changes in cytoplasmic and nuclear substrates that interact with phosphorylated extracellular signal-regulated protein kinases 1 and 2 and underscores the value of using targeted BRAF V600E animal models created through gene editing technologies., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS , KRAS , and less frequently , NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders., Methods: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF ., Results: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica., Conclusion: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

MITF E318K moderates melanoma risk. Only five MITF E318K homozygous cases have been reported to date, one in association with melanoma. This novel report uses 3D total-body-photography (TBP) to describe the dermatological phenotype of a homozygous MITF E318K individual. The case, a 32-year-old male, was diagnosed with his first of six primary melanomas at 26 years of age. Five melanomas were located on the back and one in the groin. Two were superficial spreading. Three arose from pre-existing naevi and one was a rare naevoid melanoma. 3D-TBP revealed a high naevus count (n = 162) with pigmentation varying from light to dark. Most naevi generally (n = 90), and large (>5 mm diameter) and clinically atypical naevi specifically were located on the back where sun damage was mild. In contrast, naevi count was low (n = 25 total) on the head/neck and lower limbs where sun damage was severe. Thus, melanoma location correlated with naevi density, rather than degree of sun damage. In addition to the MITF E318K homozygosity, there was heterozygosity for four other moderate-risk variants, which may contribute to melanoma risk. Further research is warranted to explore whether melanomas in E318K heterozygous and other homozygotes coincide with regions of high naevi density as opposed to sun damage. This could inform future melanoma screening/surveillance., (© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Abstract: Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen first identified in a melanoma patient and found to be expressed in most melanomas as well as in variable levels in other malignant neoplasms of epithelial, mesenchymal, or hematolymphoid lineage. Detection of PRAME expression in formalin-fixed paraffin-embedded tissue is possible by immunohistochemistry (IHC) with commercially available monoclonal antibodies. In situ and invasive melanoma frequently show a diffuse pattern of nuclear PRAME immunoreactivity which contrasts with the infrequent and typically nondiffuse staining seen in nevi. In many challenging melanocytic tumors, results of PRAME IHC and other ancillary tests correlate well, but not always: The tests are not interchangeable. Most metastatic melanomas are positive for PRAME, whereas nodal nevi are not. Numerous studies on PRAME IHC have become available in the past few years with results supporting the value of PRAME IHC as an ancillary tool in the evaluation of melanocytic lesions and providing insights into limitations in sensitivity and specificity as well as possible pitfalls that need to be kept in mind by practicing pathologists., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Nevus spilus (NS) is composed of multiple types that characterized by a congenital hyperpigmented patch within variable even superimposed lesions originating from melanocytic lineage cells. The molecular mechanism and classification of diverse NS phenotypes remain unclear. Five children with a phenotype of NS were genotyped by the panel based on next-generation sequencing in this study. DNA from biopsies, blood samples and hair follicle were sequenced to confirm the presence of a somatic mutation. Sequencing results indicated somatic mutation in the gene of NRAS or HRAS in all biopsies from the nevi, and the pathogenic variants were not detected in the samples of blood and hair follicle. This study successfully identified the somatic mutation in five unrelated children with diverse NS phenotypes. Moreover, it provided typical images and differential diagnoses between variable NS phenotypes in clinical, pathological, and genetic features, and first proposed a clinical diagnostic algorithm that contributed to simplifying and optimizing the diagnoses and management of these overlapped diseases., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Schimmelpenning-Feuerstein-Mims syndrome (SFMS), an epidermal nevus disease, features skin lesions including craniofacial nevus sebaceous and extracutaneous anomalies (e.g. brain, eye, and bone). Recent genetic studies implicate HRAS, KRAS, and NRAS genes in somatic mutations. Our case, a 48-year-old man, presented with nevus sebaceous on the scalp; pigmented skin lesions on the right side of his neck, back, and chest along the Blaschko lines; a history of epilepsy; and mild intellectual disability. Accordingly, SFMS was suspected. DNA analysis of nevus sebaceous skin and peripheral blood leukocytes showed a pathogenic HRAS variant NM_005343.4:c.34G > A p.(Gly12Ser) in biopsy specimens from different skin layers but not blood, indicating somatic mosaic mutation. Until now, the HRAS p.(Gly12Ser) mutation has been reported in somatic RASopathies but not SFMS. The authors report this mutation in a case of SFMS, review another 15 cases of SFMS, and discuss HRAS c.34G > A p.(Gly12Ser) somatic mutations. RAS mutations of somatic RASopathies share activating hotspot mutations found in cancers, and produce different phenotypes depending on the developmental stage at which the somatic mutations occur., (© 2023 Japanese Dermatological Association.)

Background: Distinguishing cutaneous malignant melanoma (CMM) from nevi can be clinically challenging. Suspicious lesions are therefore excised, resulting in many benign lesions being removed surgically to find 1 CMM. It has been proposed to use tape strip derived ribonucleic acid (RNA) to distinguish CMM from nevi., Objective: To develop this technique further and validate if RNA profiles can rule out CMM in clinically suspicious lesions with 100% sensitivity., Methods: Before surgical excision, 200 lesions clinically assessed as CMM were tape stripped. Expression levels of 11 genes on the tapes were investigated by RNA measurement and used in a rule-out test., Results: Histopathology showed that 73 CMMs and 127 non-CMMs were included. Our test correctly identified all CMMs (100% sensitivity) based on the expression levels of 2 oncogenes, PRAME and KIT, relative to a housekeeping gene. Patient age and sample storage time were also significant. Simultaneously, our test correctly excluded CMM in 32% of non-CMM lesions (32% specificity)., Limitations: Our sample contained a very high proportion of CMMs, perhaps due to inclusion during COVID-19 shutdown. Validation in a separate trial must be performed., Conclusion: Our results demonstrate that the technique can reduce removal of benign lesions by one-third without overlooking any CMMs., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Nevus sebaceous (NS) is a congenital hamartoma associated with an increased risk of secondary neoplasms in approximately 10%-20% of patients. However, additional genomic alterations underlying tumorigenesis in NS lesions have not been clarified. We performed whole-exome sequencing of archived tumor tissues (n = 8; six basal cell carcinomas and two trichoepitheliomas) and matched germline tissues (n = 7) with from seven patients with secondary tumors arising from NS. We also analyzed NS lesions without secondary tumors (n = 8). Somatic mutations and copy number alterations (CNAs) were analyzed. We identified a median of 129 somatic mutations (corresponding to 2.6/Mb in target regions, range 26-336) for eight tumors, while a median of 118 somatic mutations (2.3/Mb, range 1-196) for eight NS lesions. Known RAS hotspot mutations were found in seven of the eight tumors (six for HRAS p.G13R and one for HRAS p.Q61R) and in six of the eight NS lesions (four for HRAS p.G13R, one for KRAS p.G12C, and one KRAS p.G12D). Except RAS mutations, several putative driver mutations were detected in tumors: TP53 p.F134L/p.R213*, MYCN p.P59L, OR2Z1 p.P167S, PTPN14 p.Q768*, and SMO p.W535L. As for CNAs, two tumors harbored copy-loss in regions encompassing PTCH1 gene. However, eight NS lesions did not harbor both putative driver mutations and CNAs. In conclusion, our study revealed that secondary tumors arising from NS harbor known RAS hotspot mutations and additional genomic alterations, including putative driver mutations and PTCH1 copy-loss. These results could help to define the high-risk group for tumor development in patients with NS and provide evidence for prophylactic resection., (© 2023 Japanese Dermatological Association.)

Early detection and treatment of melanoma, the most aggressive skin cancer, improves the median 5-year survival rate of patients from 25% to 99%. Melanoma development involves a stepwise process during which genetic changes drive histologic alterations within nevi and surrounding tissue. Herein, a comprehensive analysis of publicly available gene expression data sets of melanoma, common or congenital nevi (CN), and dysplastic nevi (DN), assessed molecular and genetic pathways leading to early melanoma. The results demonstrate several pathways reflective of ongoing local structural tissue remodeling activity likely involved during the transition from benign to early-stage melanoma. These processes include the gene expression of cancer-associated fibroblasts, collagens, extracellular matrix, and integrins, which assist early melanoma development and the immune surveillance that plays a substantial role at this early stage. Furthermore, genes up-regulated in DN were also overexpressed in melanoma tissue, supporting the notion that DN may serve as a transitional phase toward oncogenesis. CN collected from healthy individuals exhibited different gene signatures compared with histologically benign nevi tissue located adjacent to melanoma (adjacent nevi). Finally, the expression profile of microdissected adjacent nevi tissue was more similar to melanoma compared with CN, revealing the melanoma influence on this annexed tissue., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and FGF23-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels. This study aims to elucidate whether the source of FGF23 excess in CSHS is RAS mutation-bearing bone or skin lesions. Toward this end, we analyzed the expression and activity of Fgf23 in two mouse models expressing similar HRAS/Hras activating mutations in a mosaic-like fashion in either bone or epidermal tissue. We found that HRAS hyperactivity in bone, not skin, caused excess of bioactive intact FGF23, hypophosphatemia, and osteomalacia. Our findings support RAS-mutated dysplastic bone as the primary source of physiologically active FGF23 excess in patients with CSHS. This evidence informs the care of patients with CSHS, arguing against the practice of nevi removal to decrease circulating, physiologically active FGF23.

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare type of epidermal nevus involving the eccrine acrosyringia. It typically presents as asymptomatic linear keratotic papules and plaques along the lines of Blaschko and predominantly affects the extremities. This disease has recently been linked to somatic mutations within the GJB2 locus. Only four GJB2 mutations have been previously documented for PEODDN, and the underlying genetic basis remains inconclusive. Herein, we report an 18-year-old female with a hyperkeratotic plaque on the dorsa of the proximal interphalangeal joint of her right ring finger, as well as multiple small hyperkeratotic papules linearly distributed on the lateral sides of her fingers occurring since birth. Histopathological results revealed prominent parakeratotic cornoid lamella-like tiers at the opening of the eccrine secretory ducts. Whole-exome sequencing of the affected skin tissue revealed a heterozygous germline mutation and a postzygotic somatic mutation in GJB2. In summary, this study presents a case of PEODDN with compound heterozygous mutations in GJB2, which broadens the genetic spectrum of this disease entity and implies a possible role for second-hit mutations in the pathogenesis of PEODDN., (© 2022 Japanese Dermatological Association.)

Background: Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant, lethal male disorder caused by mutations to the NSDHL (NAD(P)H steroid dehydrogenase-like protein) gene. It primarily exhibits strictly unilateral congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral limb defects in female individuals., Methods: A Chinese couple suffering from recurrent spontaneous abortion in male fetuses was enrolled in this study. Chromosomal microarray analysis and whole-exome sequencing were performed for genetic etiological diagnosis., Results: A 33-year-old pregnant woman with recurrent spontaneous abortion was experiencing her third pregnancy with a male embryo. In this pregnancy, a miscarriage occurred at a gestational age of 10 +6  weeks with no copy number variants. However, a novel mutation c.790-6C>T in the NSDHL gene was observed in the fetus through whole-exome sequencing (WES). Parental verification indicated that the NSDHL gene variant was inherited from the mother. Additionally, the variant in the NSDHL gene was absent in her subsequent pregnancy with a female fetus., Conclusion: In this study, we detected c.790-6C>T, a novel variant in the NSDHL gene that results in recurrent miscarriage in males. Our study may broaden the scope of research on the NSDHL gene in CHILD syndrome and strengthens the application value of WES for the genetic etiological identification of recurrent miscarriage., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Dermatologists frequently see patients with clinically atypical nevi and dermatopathologists interpret histologically dysplastic nevi on a near-daily basis, but there is great variability in the definition and management of such lesions. This part of the CME review focuses on information published since the previous comprehensive review (2012), with emphasis on molecular and genetic attributes of histologically dysplastic nevi and clinical management., Competing Interests: Conflict of interests None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported., Objective: To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN., Methods: We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified., Results: Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations., Conclusion: ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases., (© 2022 Wiley Periodicals LLC.)

Background: Proteus syndrome is characterized by a progressive segmental or patchy growth of bone, skin, adipose tissue, and central nervous system, associated with a wide range of neoplasms, pulmonary pathology, and thrombotic risk. The main histological findings are diffuse patchy overgrowth of skin and subcutaneous tissue, plantar cerebriform connective tissue nevus, and ossification defects. Case report: We present a patient that met the clinical and histological criteria necessary for the diagnosis of the disease. He required multiple surgical interventions, including amputation of the right foot. Genetic evaluation confirmed an AKT1 mutation. Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt. Although the clinical criteria and histologic findings are indicative, the diagnostic confirmation of this entity is genetic.

Background: Epidermal nevus syndrome is a group of congenital neuroectodermal and/or mesodermal disorders characterized by the epidermal nevi in common association with cerebral, eye, skeletal, cardiovascular, and renal abnormalities. Epidermal nevus syndrome is a rare syndrome, and epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction is even rarer and has not been reported to the best of our knowledge., Case Presentation: We report the case of a 10-month-old Chinese female patient who presented to our pediatric neurologic department, University of Wenzhou medical teaching Hospital, Hangzhou. She has mobility disorders on the right limbs and recurrent seizures. She had congenital disorder accompanied by brownish-black and verrucose plaques on the right side of the face as well as extensive brownish-black plaques and brown nevi on the right side of the trunk and the right arm. Epidermal nevus syndrome was diagnosed on the basis of her symptoms. Somatic sebaceous nevi and hypoplastic defects of skin, cerebra, eyes, skeleton, and cardiovascular and renal system were observed. However, in addition to the typical clinical characteristics, the patient also has a mutation (c.109G > T) in PTCH1 gene and cerebral infarction. We present a novel case report and literature review., Conclusion: To our knowledge, epidermal nevus syndrome with a mutation of PTCH1 gene and cerebral infarction has not been reported previously. This case report may contribute to characterizing the phenotype of epidermal nevus syndrome, help clinicians be aware of the association of this condition with PTCH1 gene and cerebral infarction, raise clinical suspicion, and improve early therapy., (© 2022. The Author(s).)

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus (EN) syndrome, featured by co-occurrence of speckled lentiginous nevus (SLN) and nevus sebaceous (NS). The underlying mechanism has not been clarified. Pathogenic mutations in HRAS, KRAS and BRAF gene are recently recognized as the genetic cause of PPK. Here we present a case of Chinese PPK with a mosaic mutation in HRAS gene. Physical examination of the 4-year-old male proband showed NS locating on the scalp, with EN and SLN on trunk and extremities. Except congenital fundus vascular tortuosity, no evidence of extracutaneous abnormalities was found in this case. A rare heterozygous missense c. 181 C>A mosaic mutation in HRAS was identified in samples from NS, EN and pigmented nevus using next-generation sequencing and Sanger sequencing. Meanwhile, no mutation was found in the non-lesion skin, hair follicle, or blood DNA. Recent breakthrough in clinical manifestation, genetic mutation and prognosis of PPK is also reviewed., (© 2022 Japanese Dermatological Association.)

Acquired melanocytic nevi grow and persist in a stable form into adulthood. Using genome-wide methylation profiling, we evaluated 32 histopathologically and dermoscopically characterized nevi to identify the key epigenetic regulatory mechanisms involved in nevogenesis. Benign (69% globular and 31% nonspecific dermoscopic pattern) and dysplastic (95% reticular/nonspecific dermoscopic pattern) nevi were dissimilar, with only two shared differentially methylated loci. Benign nevi showed an increase in both genome-scale methylation and methylation of Alu/LINE-1 retrotransposable elements, a marker of genomic stability, as well as global methylation. In contrast, dysplastic nevi showed evidence for genomic instability through the hypomethylation of Alu/LINE-1 (Alu: P = 0.00019; LINE-1: P = 0.000035). Using dermoscopic classifications, reticular/nonspecific patterned nevi had 59,572 5'-C-phosphate-G-3' differentially methylated loci (Q < 0.05), whereas globular nevi had no significant differentially methylated loci. In reticular/nonspecific patterned nevi, the tumor suppressor PTEN had the greatest proportion of hypermethylated 5'-C-phosphate-G-3' loci in its promoter region than all other assayed gene promoters. The relative activity of reticular/nonspecific nevi was evidenced by 50,720 hypomethylated loci being enriched for accessible chromatin and 8,852 hypermethylated loci strongly enriched, for example, marks of active gene promoters, which suggests that gain of DNA methylation observed in these nevus types plays a role in gene regulation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Melanoma is commonly driven by activating mutations in the MAP kinase BRAF; however, oncogenic BRAF alone is insufficient to promote melanomagenesis. Instead, its expression induces a transient proliferative burst that ultimately ceases with the development of benign nevi comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that restrain nevus melanocyte proliferation remain poorly understood. Here we utilize cell and murine models to demonstrate that oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway, both in melanocytes in vitro and nevus melanocytes in vivo. Mechanistically, we show that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome doubling events, which independently reduce RhoA activity to promote Hippo activation. We also demonstrate that functional impairment of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly form melanomas. Our data reveal that the Hippo pathway enforces the stable arrest of nevus melanocytes and represents a critical barrier to melanoma development., (© 2022. The Author(s).)

Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk-marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29-1.55; QSkin OR 1.58, 95% CI: 1.29-1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33-1.44; QSkin OR 1.20, 95% CI: 1.05-1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28-1.55; QSkin OR 1.44, 95% CI: 1.19-1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases., (© 2021 UICC.)

Ichthyosis and deafness syndrome is a group of devastating genodermatoses caused by heterozygous mutations in GJB2, encoding the gap junction protein connexin 26. These syndromes are characterized by severe skin disease, hearing loss, recurrent infections, and cutaneous neoplasms. Cutaneous somatic mutations in the same gene are associated with porokeratotic eccrine ostial dermal duct nevus. Here we report a family in which a parent presented with localized epidermal nevus and his child suffered with hystrix-like ichthyosis with deafness. Histologic examination of the parent's cutaneous lesion revealed verrucous epidermal nevus without features of porokeratotic eccrine ostial dermal duct nevus. Genetic analysis identified the same pathogenic variant, GJB2 c.148G>A (p.D50N), in DNA extracted from the parent's cutaneous lesion and the child's leukocytes, but not in the parent's leukocytes. This study expands the phenotypic heterogeneity of GJB2 mosaic variants in addition to porokeratotic eccrine ostial dermal duct nevus, and emphasizes the importance of molecular diagnosis of mosaic skin diseases considering the risk of severe inherited diseases in the offspring., (© 2021 Japanese Dermatological Association.)

The work-up of melanocytic tumors has undergone significant changes in the last years following the exponential growth of molecular assays. For the practicing pathologist it is often difficult to sort through the myriad of different tests available currently for clinical use. The molecular tests used in melanocytic pathology can be broadly divided into 4 categories: (i) Tests useful in the differential diagnosis of nevus versus melanoma (primarily used as an aid in the diagnosis of histologically ambiguous melanocytic tumors), (ii) Tests that predict prognosis in melanoma, (iii) Tests useful in the classification of melanocytic tumors and (iv) Tests that predict response to systemic therapy in melanoma. This review will present an updated overview of major ancillary tests used in clinical practice., (© 2021 John Wiley & Sons Ltd.)

This article reviews the clinical findings of epidermal nevi and their associated syndromes and provides an update on their pathogenic genetic changes as well as targeted therapies detailed to date., Competing Interests: Disclosure The authors have no relevant conflicts of interests to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mixed vascular naevus (MVN) is characterized by the co-occurrence of telangiectatic capillary malformation and naevus anaemicus, which can appear as a pure cutaneous phenotype or be combined with systemic manifestations such as brain malformations, neurological abnormalities and musculoskeletal disorders. Recently, GNA11 and GNAQ somatic mutations have been reported in some patients with isolated and syndromic MVN. We report three children with MVN syndrome with generalized cutaneous manifestations and a number of systemic associations not reported to date, including ophthalmological anomalies, musculoskeletal abnormalities such as Sprengel deformity and posterior vertebral fusion anomalies, and septal heart defects. We also confirm a somatic mutation of GNA11 in both telangiectatic naevus and naevus anaemicus in two of our patients and discuss a possible common pathogenic mechanism underlying the different manifestations of the syndrome. Currently, there are no guidelines for the evaluation of patients with MVN syndrome, but according to the different known aspects of the disease, a complete clinical examination should be made, and complementary laboratory and imaging tests should be considered., (© 2021 British Association of Dermatologists.)

Epidermolytic ichthyosis and epidermolytic nevi share the same histopathological features of epidermolytic hyperkeratosis, characterized by distinctive vacuolar degeneration and hypergranulosis of the superficial epidermis. Both are caused by pathogenic variants in either of two keratin genes KRT1or KRT10, with epidermolytic ichthyosis presenting as a generalized phenotype and epidermolytic nevi presenting as a mosaic phenotype. We report a boy who presented as epidermolytic ichthyosis, with diffuse erythema, superficial erosions and flaccid blisters at birth progressing to generalized ichthyosis. He was found to have inherited a novel KRT1 variant from his mother who presented with extensive epidermolytic nevi or mosaic form of epidermolytic ichthyosis, with extensive, linear and Blaschkoid verrucous, hyperkeratotic plaques over the trunk and limbs. This case highlights the importance of recognising post-zygotic mosaicism which might be transmitted to a child, and the different presentations for germline and mosaic carriers., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Postzygotic mutations in FGFR2 have been identified in mosaic forms of acne, keratinocytic epidermal nevi, nevoid acanthosis nigricans / rounded and velvety epidermal nevus and in two fetuses with papillomatous pedunculated sebaceous nevus (PPSN)., Objectives: To determine the clinical and genetic characteristics of children with cerebriform, papillomatous and pedunculated variants of sebaceous nevi., Methods: Infants diagnosed with sebaceous nevi characterized by a cerebriform, papillomatous and/or pedunculated morphology over a 10-year period (2010-2019) at three paediatric dermatology centres in Switzerland and France were included in this case series. Clinical and histological characteristics were assessed. Next-generation sequencing was used to assess for FGFR2 mutations., Results: All nevi were located on the head, with a rounded or linear shape and a typical cerebriform, sometimes papillomatous and pedunculated, surface. No associated extracutaneous anomalies were found. Nevi harboured postzygotic mutations in the transmembrane domain of FGFR2 in 6/8 children (75%), either the known specific p.(Cys382Arg) mutation in 5 cases, or a novel mutation, p.(Val395Asp), in one., Conclusions: We found an exquisite genotype-phenotype correlation in these rare nevi, with specific postzygotic mutations in the transmembrane domain of FGFR2. As not all lesions were truly papillomatous and pedunculated, the term cerebriform sebaceous nevus (CSN) appears more suitable than PPSN to describe this entity. The cerebriform pattern of CSN is reminiscent of cutis gyrata, as seen in Beare-Stevenson syndrome, which is caused by closely related germline FGFR2 mutations. While clinically impressive, CSN seem to carry a good prognosis and a low risk for extracutaneous associations., (© 2021 European Academy of Dermatology and Venereology.)

Aim: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-miRNA signature (MEL38) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign nevi to metastatic melanoma spectrum is examined. Patients & methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin-fixed paraffin-embedded biopsies of nevi, melanoma in situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analyzed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx class V or more advanced) from lower-risk skin lesions (class I-IV) with an area under the curve of 0.97 (p < 0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0-IV disease. Using an optimized classification threshold of ≥2.7 accurately identifies higher-risk melanomas with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to Spitz nevi reveals an intrasubtype profile, with elements in common to both nevi and melanoma. Conclusion: Melanoma-specific circulating miRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The MEL38 signature is an accurate and reproducible metric of melanoma status, based on changes in miRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalized genomic information about their patient's skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilization and patient outcomes.

As one of the epidermal nevus syndromes, Schimmelpenning-Feuerstein-Mims (SFM) is characterized by craniofacial nevus sebaceous (NS) and extracutaneous abnormalities (e.g., brain, eyes, and bone). Here, we report a case of a 4-year-old boy who presented with significant skin abnormalities (NS in the scalp, extensive epidermal nevus along Blaschko's lines), ocular abnormalities (strabismus), central nervous system abnormalities (seizure and mental retardation), lymphatic dysplasia (chylous pleural and pericardial effusion), cardiac abnormalities (patent foramen ovale), urogenital system abnormalities (cryptorchidism, hypospadias), and a tumor predisposition (embryonal rhabdomyosarcoma). DNA samples from NS, rhabdomyosarcoma, and peripheral blood leukocytes were analyzed by next-generation sequencing. A novel mutation in the HRAS gene (c.38G>T; p.Gly13Val) was detected in a mosaic state in NS, rhabdomyosarcoma, and peripheral blood leukocytes, with different ratio of heterozygous mutation (HRAS c.38G>T) of 39.90% (9412/23 588 reads), 73.03% (205 562/281 468 reads), and 14.16% (15 837/111 842 reads), respectively. By predicting the impact of the mutation on the biological function of protein, we found that the novel HRAS mutation (c.38G>T; p.Gly13Val) had the highest damaging scores among other HRAS mutations reported so far. This is the first reported SFM syndrome patient with novel mosaic HRAS mutation, which may help to expand the mutational spectrum of HRAS and better understand the role of HRAS in the disease., (© 2021 Japanese Dermatological Association.)

Genetic susceptibility to nevi may affect the risk of developing melanoma, since common and atypical nevi are the main host risk factors implicated in the development of cutaneous melanoma. Recent genome-wide studies defined a melanoma polygenic risk score based on variants in genes involved in different pathways, including nevogenesis. Moreover, a predisposition to nevi is a hereditary trait that may account for melanoma clustering in some families characterized by cases with a high nevi density. On the other hand, familial melanoma aggregation may be due to a Mendelian inheritance of high/moderate-penetrance pathogenic variants affecting melanoma risk, regardless of the nevus count. Based on current knowledge, this review analyzes the complex interplay between nevi and melanoma predisposition in a familial context. We review familial melanoma, starting from Whiteman's divergent pathway model to overall melanoma development, distinguishing between nevi-related (cases with a high nevus count and a high polygenic risk score) and nevi-resistant (high/moderate-penetrance variant-carrier cases) familial melanoma. This distinction could better direct future research on genetic factors useful to identify high-risk subjects.

Background/objective: Proteus syndrome, caused by a mosaic activating AKT1 variant, typically presents in toddlers with progressive, asymmetric overgrowth of the skin and bones. We aimed to define the spectrum of dermatologic disease in individuals with genetically confirmed Proteus syndrome., Methods: We conducted a retrospective review of records from dermatologic examinations of individuals evaluated at the NIH with a molecular diagnosis of Proteus syndrome. The types, prevalence, and localization of dermatologic findings were assessed., Results: Fifty-one individuals (29 males, 22 females, mean age: 9 years) with clinical features of Proteus syndrome had the mosaic c.49G>A, p.Glu17Lys AKT1 variant. Fifty (98%) had at least one cutaneous feature constituting current clinical diagnostic criteria, including vascular malformations in 42 (82%), epidermal nevus in 41 (80%), volar cerebriform connective tissue nevi in 34 (67%), and adipose dysregulation in 30 (59%). Forty-nine (96%) had at least one dermatologic finding not included within the diagnostic criteria, including confluent volar skin-colored to hypopigmented papules or nodules (n = 33, 65%), papules or nodules on the digits or face (n = 27, 53%), and nonlinear epidermal nevi (n = 15, 29%). Other frequently observed features include nail changes (n = 28, 55%), hyperpigmented macules (n = 27, 53%), patchy dermal hypoplasia (n = 18, 35%), gingival/oral mucosal overgrowth (n = 17, 33%), hypopigmented macules (n = 16, 31%), dental enamel changes (n = 9, 18%), acrochordons (n = 6, 12%), and lingual overgrowth (n = 4, 8%)., Conclusions: The range of mucocutaneous features occurring in Proteus syndrome is broader than previously considered. These observations may assist in earlier diagnosis and management and provide novel insights regarding the pathogenesis of the condition., (© Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Importance: Acral skin may develop nevi, but their mutational status and association with acral melanoma is unclear., Objective: To perform targeted next-generation sequencing on a cohort of acral nevi to determine their mutational spectrum., Design, Setting, and Participants: Acral nevi specimens (n = 50) that had been obtained for diagnostic purposes were identified from the pathology archives of a tertiary care academic cancer center and a university dermatology clinic. Next-generation sequencing was performed on DNA extracted from the specimens, and mutations called. A subset of samples was stained immunohistochemically for the BRAF V600E mutation., Results: A total of 50 nevi from 49 patients (19 males and 30 females; median [range] age, 48 [13-85] years) were examined. Analysis of the sequencing data revealed a high prevalence of BRAF mutations (n = 43), with a lower frequency of NRAS mutations (n = 5). Mutations in BRAF and NRAS were mutually exclusive., Conclusions and Relevance: In this cohort study, nevi arising on mostly sun-protected acral skin showed a rate of BRAF mutation similar to that of acquired nevi on sun-exposed skin but far higher than that of acral melanoma. These findings are in contrast to the well-characterized mutational landscape of acral melanoma.

The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pH e ), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN). We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4. Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker. Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN. Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets.

Background: CLOVES syndrome (OMIM# 612918) is a rare overgrowth disorder resulted from mosaic gain-of-function mutations in the PIK3CA gene. All the reported CLOVES-associated PIK3CA mutations are missense mutations affecting certain residues. We aim to investigate underlying mutation and its pathogenicity in a patient with CLOVES syndrome and to evaluate the inhibitory effects of the PI3K/AKT/mTOR pathway inhibitors., Results: We performed whole-exome sequencing (WES) and Sanger sequencing to detect underlying somatic mutations in the skin lesion of the patient. Quantitative real-time PCR (qRT-PCR) was employed to evaluate the mRNA abundance of PIK3CA in the patient's skin lesion. AKT phosphorylation level assessed by immunoblotting of lysates from transiently transfected cells was performed to evaluate the PIK3CA mutations and inhibitory effects of PI3K/AKT/mTOR pathway inhibitors. A somatic frameshift mutation c.3206&#95;3207insG (p.X1069Trpfs*4) in PIK3CA was identified in the genomic DNA extracted from the vascular malformation sample of the patient. This mutation affects the canonical stop codon of PIK3CA (NM&#95;006218.4) and is predicted to produce a prolonged protein with four additional residues. qRT-PCR demonstrated that the mRNA expression levels of the patient's affected skin tissue were comparable compared to the normal control. In vitro studies revealed that p.X1069Trpfs*4 mutant exhibited increased AKT phosphorylation significantly to that of the wildtype, which could be inhibited by PI3K/AKT/mTOR pathway inhibitors., Conclusions: We have identified the first frameshift mutation in PIK3CA that causes CLOVES syndrome, which was confirmed to overactive PI3K/AKT/mTOR pathway by transient transfection assays. We also provided more evidence of ARQ092 to be a potential therapeutic option for PROS in vitro.